A widespread bacterial toxin reveals a deeply divergent DNase family neutralized by diverse immunity proteins.

Bacteria vie for space and resources by secreting toxin proteins into neighboring cells. Many toxins remain unidentified as they lack similarity to proteins with known functions. Researchers have now discovered Rehh, a widespread antibacterial toxin linked to various bacterial secretion systems. They demonstrate that Rehh is utilized in interbacterial competition.

Purified Rehh functions as a manganese-dependent DNase, aligning with the observation that Rehh damages the DNA of target cells, triggering the SOS response and double-strand breaks. The crystal structure of Rehh, when bound to a compatible immunity protein, reveals a positively charged histidine-rich metal-binding pocket within a protein scaffold that bears little resemblance to previously characterized nucleases.

However, a closer examination of this pocket shows it maintains the catalytic geometry typical of the HNH/His-Me-finger superfamily, indicating that Rehh is a highly distinct HNH nuclease whose evolutionary history has been obscured by extensive structural changes. The compatible immunity protein neutralizes Rehh by encompassing the catalytic pocket with an acidic surface, mimicking the electrostatic properties of the DNA phosphate backbone.

Comparative genomics further reveals that Rehh homologs are associated with numerous unrelated immunity families, suggesting that distinct immunity domains repeatedly adopt a common strategy to inhibit this toxin. These findings illustrate how conflict-driven diversification can obscure enzyme ancestry while preserving catalytic function and shed light on a potential case of convergent evolution among immunity proteins that independently take advantage of the same toxin biochemical vulnerability.